Cocaine abuse is one of the greatest concerns of the American public today, and has therefore become a focus of medical, social and political leaders. Cocaine is one of the most addictive substances known, and addicts may lose their ability to function at work or in interpersonal situations. Drug dependence and the great profits that are made throughout the distribution network of cocaine have fueled a rise in drug-associated crime in the United States and in Colombia. Although the incidence of casual cocaine use has decreased substantially in the last few years, the number of weekly users is rising. The rise has accompanied a change in the chemical form often used to free base, or xe2x80x9ccrack,xe2x80x9d and the route of administration used from nasal to inhalation by smoking or intravenous injection.
Psychological and behavioral approaches are important in a treatment program because peer pressure and environmental cues are closely associated with a relapse to addiction. However, behavioral observations have identified a window of about ten weeks after cessation of cocaine use where the susceptibility to relapse is greatest. Clearly, there is a need to increase the success rate of outpatient detoxification programs through the development of pharmacological agents that will assist during this critical period.
Currently a number of treatment strategies are being looked at using CNS agents developed for other indications. The agents being tried include, among others, the indirect dopamine agonist, amantadine, the direct agonist bromocriptine, the partial mu opiate receptor agonist, buprenorphine, and the tricyclic antidepressant, desipramine. While these agents appear to depress either self-administration or cocaine xe2x80x9ccravingxe2x80x9d under certain circumstances, these studies are still in their early stages and the efficacy of such treatments has not been established.
The behavioral properties of cocaine, including its abilities to act as a reinforcer, are thought to stem from its ability to inhibit the reuptake of dopamine (DA). While cocaine also has the ability to act as an inhibitor of serotonin and norepinephrine uptake as well as to bind to sigma opiate and muscarinic receptors, the potencies of cocaine and analogs in self-administration studies correlate best with their DA transporter inhibitor activities. Unfortunately, the precise mechanism by which cocaine inhibits dopamine uptake is still uncertain. Several laboratories have shown that cocaine inhibition of dopamine uptake into striatal synaptosomes is consistent with a classic, fully competitive mechanism. However these data are also consistent with more complex models, including allosteric or partially competitive, and several others involving steric hindrance, distinct but overlapping sites or multiple binding sites in which at least one is required for both cocaine and dopamine binding. In addition, a recent study using rotating disk electrode voltammetry, which is capable of monitoring uptake with a 50 msec resolution, suggests that cocaine inhibits dopamine uptake uncompetitively while competitively blocking Na+ and Clxe2x88x92 binding to the carrier. While these data have not been validated using other experimental approaches, they further support the idea that the cocaine and dopamine binding sites are unique.
N-Ethylmaleimide (NE) is capable of inhibiting about 95% of the specific binding of [3H]mazindol, and the effect of 10 mM N-ethylmaleimide is completely prevented by 10 xcexcM cocaine, while neither 300 xcexcM dopamine nor d-amphetamine afforded any significant protection. Furthermore, a recent study of the structure of the dopamine transporter revealed that aspartate and serine residues lying within the first and seventh hydrophobic putative membrane spanning regions were critical for dopamine uptake, but less so for [3H]CFT (WIN-35428) binding. For example, replacement of the serine residues at positions 356 and 359 in the seventh hydrophobic region by alanine or glycine reduced [3H]DA uptake, whereas [3H]CFT (WIN-35428) binding was less affected. More recent experiments with DA and NE transporter chimeras show that transmembrane domains 6-8 determine cocaine binding while domains 9-12 plus the carboxy tail are responsible for DA binding affinity. Thus, these data support the hypothesis that a significant portion of the cocaine binding domain on the dopamine transporter is distinct from that of either dopamine or amphetamine. This distinction may be sufficient to allow properly designed drugs to prevent cocaine binding without inhibiting dopamine uptake.
The most promising agents for treating cocaine abuse, may be agents which possess the ability to mimic partially the effects of cocaine, thereby helping to maintain individuals in treatment programs while they slowly withdraw from cocaine. Such an agent would function like methadone, a drug widely used in the treatment of opiate abuse. A compound with methadone-type activity against cocaine abuse is likely to be a partial agonist of cocaine; namely, a substance that elicits some of the same effects in the user as cocaine itself, but without causing the same degree of euphoria. Ideally, the compound should have little or no abuse liability.
Thus there is currently a need for therapeutic agents that can be used to treat cocaine abuse.
The present invention provides a compound of formula (I): 
wherein
Y is NR6, xe2x80x94C(R4)(R5)xe2x80x94, or xe2x80x94Oxe2x80x94;
R1 is xe2x80x94C(xe2x95x90O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1,2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(xe2x95x90O)ORb, C(xe2x95x90O)NRcRd, NReRf, or S(xe2x95x90O)nRg; and R3 is (C6-C10)aryl, 5-10 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, 5-10 membered heteroaryl(C1-C6)alkyl, (C6-C10) arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z; or
R1 is xe2x80x94CH2xe2x80x94, or xe2x80x94CH2CH2xe2x80x94, wherein R1 is attached to a carbon at the ortho position of R3; and R3 is (C6-C10)aryl, or 5-10 membered heteroaryl;
R2 is hydrogen or (C1-C6)alkyl;
R4 and R5 are independently hydrogen or (C1-C6)alkyl;
R6 is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, or S(O)2Rh;
n is 0, 1 or 2;
W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
Ra to Rg are independently hydrogen or (C1-C6)alkyl; and
Rh is H, (C1-C6)alkyl, or phenyl; or a pharmaceutically acceptable salt thereof.
Unexpectedly, it has been found that compounds of formula (I) can bind to the cocaine recognition site with an affinity comparable to that of cocaine; additionally, the compounds also act as potent inhibitors of dopamine uptake. It has been observed in drug discrimination studies in rats, that such compounds exhibit only weak cocaine- and amphetamine-like effects. The compounds of the invention thus appear to partially mimic cocaine""s discriminative stimulus effects. Of further note are the results obtained from intravenous drug self-administration studies carried out using rats. In these studies, the animals trained to self-administer cocaine failed to self-administer the present compounds. In locomotor activity studies the compounds were found to have weak motor stimulant effects. Compounds with these properties may be useful for treating drug abuse or for treating disorders wherein modulation of dopamine or serotonin uptake is desired.
The invention also provides a pharmaceutical composition comprising a compound of formula I as described herein; or a pharmaceutically acceptable salt thereof; in combination with a pharmaceutically acceptable diluent or carrier.
The invention also provides a method comprising treating drug (e.g. cocaine) addiction in a human by administering a pharmaceutically effective dose of a compound of formula I; or a pharmaceutically acceptable salt thereof.
The invention also provides a method for treating a disease or condition in a mammal in which the activity of dopamine or serotonin is implicated and modulation of dopamine or serotonin reuptake is desired (e.g. Parkinson""s disease or depression), comprising administering a compound of formula I; or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula I; or a pharmaceutically acceptable salt thereof; for use in medical therapy or diagnosis.
The invention also provides the use of a compound of formula I; or a pharmaceutically acceptable salt thereof; to prepare a medicament useful for treating drug (e.g. cocaine) addiction, Parkinson""s disease, or depression.
The invention also provides a radiolabeled compound comprising a radionuclide and a compound of formula I; or a pharmaceutically acceptable salt thereof, as well as methods for using such a radiolabeled compound as an imaging agent (e.g. to identify, or evaluate the function of, neurotransmitter binding sights in the brain of a mammal, such as a human).
The invention also provides a method comprising binding a compound of formula I to mammalian tissue comprising dopamine receptors, in vivo or in vitro, by contacting said tissue with an amount of a compound of formula I effective to bind to said receptors. Tissue comprising dopamine receptors with compounds of formula I bound thereto can be used as a pharmacologic tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with dopamine function, by contacting the agents with the tissue, and measuring the extent of displacement of the compound of formula I and/or binding of the agent. Tissue comprising dopamine receptors with compounds of formula I bound thereto can also be used generally to elucidate the physiological function of neurotransmitters.